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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the attempt to identify genes associated with metastasis, we have compared gene expressions of two metastatic cell lines, 4T1 and 66cl4, and one noninvasive, nonmetastatic cell line, 67NR, which originate from the same mouse mammary adenocarcinoma. Using the technique of differential display, we identified a novel member of the semaphorin/collapsin family in the two metastatic cell lines. We have named it M-semaH. Northern hybridization to a panel of tumor cell lines revealed transcripts in 12 of 12 metastatic cell lines but in only 2 of 6 nonmetastatic cells and none in immortalized mouse fibroblasts. To our knowledge, this is the first time that the expression of a semaphorin gene has been shown to correlate positively with tumor progression. We have characterized two transcripts present in the tumor cells. One transcript, M-semaH-v, is a putative splice variant, which is less abundant in normal tissue and lacks 478 bp in the 3' untranslated region. Both transcripts encode the same 775 amino acids with the features of a secreted glycoprotein. Northern analysis suggests that the M-semaH gene is involved in embryonic development and in situ hybridization locates the M-semaH expression to the developing lungs, to developing skeletal elements, and to the ventral horns of the developing neural tube.
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PMID:Transcription of a novel mouse semaphorin gene, M-semaH, correlates with the metastatic ability of mouse tumor cell lines. 951 11

Semaphorins, the plexin family of semaphorin receptors, and scatter factor receptors share evolutionarily conserved protein modules, such as the semaphorin domain and Met Related Sequences (MRS). All these proteins also have in common a role in mediating cell guidance cues. During development, scatter factor receptors control cell migration, epithelial tubulogenesis, and neurite extension. Semaphorins and their receptors are known signals for axon guidance; they are also suspected to regulate developmental processes involving cell migration and morphogenesis, and have been implicated in immune function and tumor progression. Scatter factors and secreted semaphorins are diffusible ligands, whereas membrane-bound semaphorins signal by cell-cell interaction. Cell guidance control by semaphorins requires plexins, alone or in a receptor complex with neuropilins. Semaphorins, besides their role in axon guidance, are expected to have multiple functions in morphogenesis and tissue remodeling by mediating cell-repelling cues through plexin receptors.
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PMID:Plexins, semaphorins, and scatter factor receptors: a common root for cell guidance signals? 1063 62

Neuropilin-2 (np-2) is a receptor for semaphorin-3F (sema-3F) and semaphorin-3C (sema-3C). These semaphorins repel tips of growing axons that express np-2. In addition, np-2 functions as a receptor for heparin binding forms of the angiogenic factor vascular endothelial growth factor (VEGF) such as VEGF145 and VEGF165. We report that np-2 is strongly expressed in neuroendocrine cells located all along the human digestive tract. Confocal fluorescent microscopy revealed that np-2 is concentrated in vesicle-like structures located near the nucleus at the basolateral side of these cells. In the colon, the np-2-expressing subpopulation of neuroendocrine cell is almost identical with the serotonin-producing subpopulation of neuroendocrine cells. Gastrointestinal carcinoid tumors are digestive tract tumors that develop from neuroendocrine cells. Interestingly, most of the carcinoid tumors derived from the colon and the appendix did not contain np-2-producing cells. However, some carcinoid tumors derived from the small intestine and stomach did express low levels of np-2 in isolated foci of cells. By contrast, strong serotonin and chromogranin-A expression was observed in all of the carcinoid tumors that were examined. These results suggest that loss of np-2 expression may accompany tumor progression in carcinoid tumors.
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PMID:Neuroendocrine cells along the digestive tract express neuropilin-2. 1139 92

The semaphorins are the products of a large family of genes currently containing more than 30 members. These genes are divided into eight classes of which classes 1, 2 and 8 contain invertebrate and viral semaphorins, while classes 3-7 contain the vertebrate semaphorins. The semaphorins have been implicated in diverse developmental processes such as axon guidance during nervous system development and regulation of cell migration. Plexin receptors function as binding and signal transducing receptors for all semaphorins except for the class-3 semaphorins which bind to neuropilins which subsequently activate signaling through associated plexins. The class-3 semaphorins semaphorin-3B (s3b) and semaphorin-3F (s3f) function additionally as potent inhibitors of tumor development in small cell lung carcinoma. Recent evidence indicates that these semaphorins modulate the adhesive and migratory properties of responsive malignant cells. S3f as well as semaphorin-3A (s3a) were also found to function as inhibitors of angiogenesis, and it was shown that the anti-angiogenic properties of s3f contribute significantly to its anti-tumorigenic properties. In contrast with these inhibitory semaphorins, there is some evidence indicating that semaphorins such as semaphorin-3C (s3c), semaphorin-3E (s3e), semaphorin-4D (s4d), semaphorin-5C (s5c) semaphorin-6A (s6a) and semaphorin-6b (s6b) may contribute to tumorigenesis or to tumor progression. In this review we discuss the semaphorins, their receptors and their signal transduction mechanisms, and evidence linking semaphorins to the control of tumorigenesis and tumor progression.
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PMID:Semaphorins in cancer. 1556 15

Semaphorins, first described as axon guidance molecules, play an essential role in neural development, angiogenesis and immunological response. In 1996, two semaphorin genes, SEMA3B and SEMA3F, were isolated from chromosomal region 3p21.3 believed to contain a tumor suppressor gene based on frequent loss of heterozygosity in lung and breast cancer. Since these first studies, several semaphorins have been involved in tumor progression. Some semaphorins have been proposed to have pro-tumoral properties, whereas others have been shown to have tumor suppressive activity. This review summarizes the most recent data implicating semaphorins in cancers.
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PMID:[Semaphorins and cancers : an up 'dating']. 1598 8

We have previously shown that the expression of a semaphorin, known as a repelling cue in axon guidance, Sema3E, correlates with the ability to form lung metastasis in murine adenocarcinoma cell models. Now, besides providing evidence for the relevance of SEMA3E to human disease by showing that SEMA3E is frequently expressed in human cancer cell lines and solid tumors from breast cancer patients, we show biological activities of Sema3E, which support the implication of Sema3E in tumor progression and metastasis. In vivo, expression of Sema3E in mammary adenocarcinoma cells induces the ability to form experimental lung metastasis, and in vitro, the Sema3E protein exhibits both migration and growth promoting activity on endothelial cells and pheochromocytoma cells. This represents the first evidence of a metastasis-promoting function of a class 3 semaphorin, as this class of genes has hitherto been implicated in tumor biology only as tumor suppressors and negative regulators of growth. Moreover, we show that the full-size Sema3E protein is converted into a p61-Sema3E isoform due to furin-dependent processing, and by analyzing processing-deficient and truncated forms, we show that the generation of p61-Sema3E is required and sufficient for the function of Sema3E in lung metastasis, cell migration, invasive growth, and extracellular signal-regulated kinase 1/2 activation of endothelial cells. These findings suggest that certain breast cancer cells may increase their lung-colonizing ability by converting the growth repellent, Sema3E, into a growth attractant and point to a type of semaphorin signaling different from the conventional signaling induced by full-size dimeric class 3 semaphorins.
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PMID:Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis. 1602 18

The neuropilins were originally described as receptors for the six axon guidance factors belonging to the class-3 semaphorins. They were subsequently found to function in addition as receptors for specific splice forms of angiogenic factors belonging to the VEGF family. The neuropilins are expressed in many types of cancer cells, in endothelial cells and in additional many types of normal diploid cell types. Recent findings indicate that the neuropilins and their associated plexin and tyrosine-kinase VEGF receptors play a regulatory role in developmental angiogenesis as well as in tumor angiogenesis. The neuropilin ligands belonging to the semaphorin family as well as the various VEGF's function as modulators of angiogenesis and tumor angiogenesis. Furthermore, since many types of cancer cells express neuropilins and neuropilin associated receptors, it is not surprising that various neuropilin ligands can modulate the behavior of cancer cells directly leading to the potentiation or inhibition of tumor progression.
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PMID:The neuropilins and their role in tumorigenesis and tumor progression. 1635 25

An important aspect of tumor progression is the ability of cancer cells to escape detection and clearance by the immune system. Recent studies suggest that several tumors express soluble factors interfering with the immune response. Here, we show that semaphorin-3A (Sema-3A), a secreted member of the semaphorin family involved in axonal guidance, organogenesis, and angiogenesis, is highly expressed in several tumor cells. Conditioned media of Sema-3A-transfected COS-7 cells or human recombinant Sema-3A inhibited primary human T-cell proliferation and cytokines production under anti-CD3 plus anti-CD28 stimulating conditions. Sema-3A also inhibited the activation of nonspecific cytotoxic activity in mixed lymphocyte culture (MLC), as measured against K-562 cells. In contrast, suppression of Sema-3A in tumor cells with a small interfering RNA (siRNA) augmented T-cell activation. The inhibitory effect of Sema-3A in T cells is mediated by blockade of Ras/mitogen-activated protein kinase (MAPK) signaling pathway. The presence of Sema-3A increased the activation of the Ras family small GTPase Rap1 and introduction of the dominant-negative mutant of Rap1 (Rap1N17) blunted the immunoinhibitory effects of Sema-3A. These results suggest that Sema-3A inhibits primary T-cell activation and imply that it can contribute to the T-cell dysfunction in the tumor microenvironment.
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PMID:Semaphorin-3A is expressed by tumor cells and alters T-cell signal transduction and function. 1638 Apr 53

The semaphorin family consists of soluble and membrane-bound proteins originally identified as axonal guidance cues functioning during neuronal development. However, it is becoming increasingly clear that semaphorins play diverse roles in organogenesis, vascular growth, and tumor progression. In addition, emerging evidence indicates that several semaphorins, called "immune semaphorins," play crucial roles also during immune responses. Extensive studies on the immune semaphorins have revealed not only parallels but also differences in the semaphorin functions between the immune and nervous systems, providing unexpected but meaningful insights into the biological activities of these molecules. This chapter focuses on our current understanding of the roles of semaphorins and their receptors in the immune system.
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PMID:Immune semaphorins: increasing members and their diverse roles. 1738 40

The semaphorins constitute a large family of molecular signals with regulatory functions in neuronal development, angiogenesis, cancer progression and immune responses. Accumulating data indicate that semaphorins might trigger multiple signalling pathways, and mediate different and sometimes opposing effects, depending on the cellular context and the particular plexin-associated subunits of the receptor complex, which can include receptor-type or cytoplasmic tyrosine kinases such as MET, ERBB2, VEGFR2, FYN, FES, PYK2 and SRC. It has also been shown that a specific plexin can alternatively associate with different tyrosine kinase receptors, eliciting divergent signalling pathways and functional outcomes. Tyrosine phosphorylation is a pivotal post-translational protein modification that regulates intracellular signalling. Therefore, phosphorylation of tyrosines in the intracellular domain of plexins could determine or modify their interactions with additional signal transducers. Here, we discuss the potential relevance of tyrosine phosphorylation in semaphorin-induced signalling, with an emphasis on its probable role in dictating the choice between multiple pathways and functional outcomes. The identification of implicated tyrosine kinases will pave the way to target individual semaphorin-mediated functions.
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PMID:Tyrosine phosphorylation in semaphorin signalling: shifting into overdrive. 1866 Jul 49


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